Cyanoacetylenes as Triggers and Partners in KOH-Assisted Assemblies of Quinoline-Based Dihydropyrimido[1,2- a]quinolin-3-ones on Water

Article abstract of DOI:10.1021/acs.joc.9b01482

Arylcyanoacetylenes trigger the assembly of dihydropyrimido[1,2-a]quinolin-3-ones in good to excellent yields on the platform of quinolines in the presence of KOH in aqueous media at room temperature. This green on-water methodology provides a simple one-pot access to a novel family of the pharmaceutically prospective compounds.

Full text of DOI:10.1021/acs.joc.9b01482

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Article
Cyanoacetylenes as Triggers and Partners in KOH-assisted Assemblies
of Quinoline-Based Dihydropyrimido[1,2-a]quinolin-3-ones on Water
Kseniya V. Belyaeva, Lina P. Nikitina, Anastasiya G. Mal’kina, Andrei
V. Afonin, Alexander Valentine Vashchenko, and Boris A. Trofimov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01482 • Publication Date (Web): 02 Jul 2019
Downloaded from http://pubs.acs.org on July 2, 2019
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The Journal of Organic Chemistry
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Cyanoacetylenes as Triggers and Partners in KOH-assisted
Assemblies of Quinoline-Based Dihydropyrimido[1,2-a]quinolin-3-
ones on Water
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Kseniya V. Belyaeva, Lina P. Nikitina, Anastasiya G. Mal’kina, Andrei V. Afonin, Alexander V.
Vashchenko and Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk,
664033 Russian Federation.
KEYWORDS. Nitrogen Heterocycles, Alkynes, Water, Annulation Reaction, One Pot Synthesis.
ABSTRACT: Arylcyanoacetylenes triggers the assembly of dihydropyrimido[1,2-a]quinolin-3-ones in good to excellent
yields on the platform of quinolines in the presence of KOH in aqueous media at room temperature. This green on water
methodology provides a simple one-pot access to a novel family of the pharmaceutically prospective compounds.
INTRODUCTION
arylisocyanates are lacrimators);13 (ii) 3-(5,5-dimethyl-3-
oxocyclohex-1-enylamino)carboxylic acids, aldehydes with
malononitrile (or unsaturated dinitriles);14-16 (iii) 5-oxo-
The sustainable interest in conjugated bicyclic 6-6
systems, pyrimidoquinolines, is primarily inspired by their
structural similarity with natural biologically active
compounds, in particular with pyrimidine bases.1 Several
reviews2,3 and experimental papers4 are devoted to the
synthesis and study of the properties of pyrimido[1,2-
a]quinolines. This motif is embedded in numerous
biologically active compounds and natural products
exhibiting antibacterial, antifungal,4a,5,6 and antiallergic7
activities. The pyrimido[1,2-a]quinoline scaffold is a key
structural unit of chromophores and siderophores.2 When
the carbonyl group stands in the position 3, these
compounds are actually δ-lactams, close derivatives of
2,5-dihydroisoxazole-4-carboxylate
and
2-
chloroquinolines.17
O
OH
F
O
N
H
H
N
N
N
N
N
O
O
O
O
N
Raltegravir
anti-HIV
N
HN
N
EtO HN
N
H2N
N
N
OCH2O
H
Aciclovir
antivirial
Pr
aminoquinoline cinnamic acid, which is
a flagship
N
N
N
O
compounds in bio and medicinal chemistry.8
O
S
N
N
O
The pyrimidinone with δ-lactam moiety is a key
pharmacophore scaffold met in a number of commercially
important popular drugs for treatment of HIV
(Raltegravir),9 erectile dysfunction (Viagra, Sildenafil),10
herpes diseases (Aciclovir)11 and so forth (Figure 1).
Sildenafil
male erectile dysfunction
antiplatelet activity
Figure 1. Representative of pyrimidinone drugs and
pyrimidoquinoline bioactive compounds.
Therefore, to develop a rational environmentally healthy
strategy for fusion of the quinoline ring with pyrimidinone
cycles for construction of pyrimidoquinolinone scaffold
now is one of the challenges in pharmaceutically oriented
synthesis. One might expect that the fusion of
pyrimidinone structure with the quinoline cycle could
further enhance and extend pharmaceutically valuable
properties of such novel molecules. In this context, the
representatives of pyrimidoquinolinones were reported to
One rapidly developing trend in modern organic
chemistry is so-termed “on water” synthesis.18 Such
reactions feature numerous advantages with regard to
environmental friendliness, cost efficiency and feasibility
of implementation.19 It is not surprising because water is
an omnipresent natural substance, indispensable for all
living organisms. No wonder the organic chemistry
community is now searching for “on water” syntheses.20
possess
antiplatelet
activity.12
At
present,
RESULTS AND DISCUSSION
dihydropyrimido[1,2-a]quinolin-3-ones, still limited in
number, are assembled from: (i) quinoline, DMAD and
arylisocyanate (only one example, the reaction proceeds in
CH2Cl2, which is toxic and cancerogenic and
Here we report an environmentally benign one-pot
synthesis of dihydropyrimido[1,2-a]quinolin-3-ones based
on activation of the quinoline ring by complexing it with
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а
readily available21 arylcyanoacetylenes in a two-phase
micelle-like heterogeneous alkaline aqueous system. A
forerunner of this synthesis was our recent double one-pot
2,3-functionalization of quinolines under the action
arylacylacetylenes in a KOH/H2O/MeCN system (Scheme
1).22
b
Conditions: 1a (0.5 mmol), 2a (0.5 mmol) and H2O (0.045 mL), rt. 1a
(0.5 mmol), 2a (0.6 mmol) and H2O (0.045 mL). temperature was 55-60 oC;
1a (0.5 mmol), 2a (0.5 mmol) and H2O (0.5 mL). for homogenizations of
c
d
1
2
3
4
5
6
7
8
e
f
reaction mixture 0.25 mL MeCN were employed. 3-cyano-2-phenylquinoline
4 also was isolated in 9% yield. g NaOH was used instead of KOH
As follows from the structure of 3a, water is
incorporated in the molecule serving in this reaction not
only as solvent, but also as a reactant. Without KOH at
room temperature the process almost does not take place:
the yield of 3a is just 4% (entry 1). Upon increasing the
KOH loading to 10-20 mol%, the yield of 3a grows (to 67-
70%, entries 2, 3). At a higher KOH concentration (30
mol%), the yield does not noticeably change (66%, entry
4). At elevated temperature (55-60 oC), the reaction
expectedly proceeds faster (6 instead of 24 h), though the
yield of the target product considerably drops (29%, entry
6), meaning that side processes are accelerated faster than
the desired one. Some interference of a side reaction is
likely indicated by the higher conversion of quinoline 1a as
compared to the yields. An attempt to improve the
annulation efficiency by increasing the loading of
cyanoacetylene 2a did not lead to positive results (entry
Scheme 1. One-pot Double 2,3-Functionalyzation of
Quinolines
by
Arylacylacetylenes
in
the
KOH/H2O/MeCN System
9
Previous work
R
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60
KOH/H2O/MeCN
O
55-60 oC, 48 h
Ar
+
domino-sequence
N
O
het
R
O
het
+
Me
up to 66%
14 examples
N
Ar
Surprisingly,
this
2,3-difunctionalization
with
cyanophenylacetylene appeared to be inefficient.22a
Further systematic study of this issue led us to discovery of
new reaction, namely the annulation of quinolines with
arylcyanoacetylenes
in
water
to
assemble
1
5). Analysis of the H NMR spectra of reaction mixtures
revealed trace amounts of product of 2,3-difuctionalization
dihydropyrimido[1,2-a]quinolin-3-ones.
First, for a better understanding of the influence of
reaction condition on the yield of the target compounds,
we have chosen, as a reference, the reaction between
quinoline 1a and cyanophenylacetylene 2a in water in the
presence of KOH to afford dihydropyrimido[1,2-
a]quinolin-3-one 3a. The reaction progress was followed
by IR spectroscopy (disappearance of the C≡N absorption
band at 2262 cm-1 in the starting acetylene 2a). Selective
representative results of these experiments are given in
Table 1. Generally, at 1:1 reactant molar ratio the
of the quinoline ring, 3-cyano-2-phenylquinoline
4
(Scheme 2), i.e. the reaction like that shown in Scheme 121а
still occurs here as a minor process.
Scheme 2. Double 2,3-Functionalization of Quinoline
1a with Cyanophenylacetylene 2a
2a
H2O/KOH
CN
1a
N
OH
CN
N
Ph
N
Ph
o
H
annulation proceeds at 20-60 C to produce the target
product in 4-70% yields depending on the KOH
concentration, temperature and water content.
CN
domino-sequence
Table 1. Synthesis of Dihydropyrimido[1,2-a]quinolin-
3-one 3a: Yield/Conditions Relationship a
Ph
4
9%
H2O (KOH)
The key step of this double 2,3-functionalization of
quinoline is the hydration of the 1,3-dipolar primary
intermediate and its rearrangement to an intermediate
aminal which further undergoes multiposition domino
transformations.21a This implies that at a higher content of
H2O this reaction should be more expressed. The
experiments confirm that this assumption is true. In fact
when the reaction mixture was 10 time diluted (the KOH
loading remain the same) and the process was conducted
Ph
+
CN
N
NH
2a
N
1a
Ph
O
3a
entry
KOH
t (h)
conversion of
yield of 3a
1a (%)
(%)
(mol%)
1
2
none
10
24
24
24
24
24
6
12
77
79
83
79
83
94
91
89
83
83
4
67
70
66
64
29
66
10
51f
60
59
o
at 55-60 C, we managed to isolate product 4 in 9% yield
3
20
(entry 9).
4
30
An important feature of this reaction is that it proceeds
as a two-phase process, since the reactants, insoluble in
water, upon mixing form the organic layer wherein the
annulation occurs. When the reaction mixture was
homogenized by addition of MeCN (entry 8), the yield of
the target product sharply dropped (10%), thus indicating
the key role of the heterogeneous character of the process.
5b
6c
20
20
7d
8d,e
9c,d
10d
11
20
72
72
6
20
20
220
20g
24
24
Eventually, the following conditions for the annulation
studied may be considered as provisionally optimal ones:
1a:2a molar ratio is 1:1, 20 mol% of KOH, water, rt.
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Consequently, the substrate scope was investigated using
the conditions thus found (Scheme 3).
strong substituent effect is observed for the
lager concentration of the 1,3-dipolar adduct
1
2
3
4
5
6
7
8
quinoline/cyanoacetylene. This basicity/yield dependence
is further evidenced by the lowest yield of
pyrimidoquinolinone 3k (16%) obtained from 6-
chloroquinoline 1e having the lowest basicity (pKa for 1e
= 4.18) in the series of quinolines studied. The decreased
yield (30%) of target product 3i in the case of 4-
methylquinoline 1c is likely due to side nucleophilic
addition of C-acidic methyl group to cyanophenylacetylene,
as was previously observed23 for 2-methylquinoline. Since
the reaction mixtures represent two-phase systems, the
yield and reaction time should also depend on the reactant
composition in the organic phase, which is different for
diversely hydrophilic/hydrophobic starting compounds.
Therefore, the substituent effect in this case should be
determined not only by electronic and steric
characteristics of the reactants, but also by the physical
A
arylcyanoacetylenes 2a-f. Surprisingly, both electron-
donating and electron-withdrawing substituents in their
benzene ring decrease the yields of the target products
which are 16-70% (cf. compounds 3a-f). The reason for
such a contradiction is likely that donor substituents (Me,
Et, OEt) reduce the electrophilicity of the triple bond and
thereby lower the concentration of the primary 1,3-dipole
intermediate, while electron-withdrawing substituents
[CN, MeC(O)], on the contrary, enhance the electrophilicity
of cyanoacetylenes thus making them more reactive in
adverse side processes, e.g. oligomerization, hydration. In
this case, the reaction rate (the process duration) roughly
follows the same trend.
9
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Scheme 3. Scope of the Substrates a
properties
(the
mutual
solubility,
hydrophilic/hydrophobic balance).
R1
R1
CN
0.045 mL H2O
The reaction proves to be well extendable to the
isoquinoline series. Thus, the reaction between
isoquinoline 5 and arylcyanoacetylenes 2a,c,f under the
above optimal conditions gave pyrimidoisoquinolinones
6a-c in 50-92% yields (Scheme 4).
20 mol% KOH
+
N
NH
rt, 24-120 h
N
1a-g
O
R2
2a-f
R2
3a-m
1
1
2
a
b
c
: R = H ( ), 3-Me ( ), 4-Me ( ),
Structures of the synthesized pyrimidoquinolinones 3
d
e
f
g
and 6 were proven using H and 13C NMR spectroscopy
6-Me ( ), 6-Cl ( ), 6-OMe ( ), 5-SMe ( );
1
2
a
b
c
d
e
f
: R = H ( ), Me ( ), Et ( ), OEt ( ), CN ( ), C(O)Me ( )
data; in the case of the isoquinoline derivative 6a, X-ray
diffraction analysis was executed (Scheme 4).
Scheme 4. Synthesis of Dihydro-2H-pyrimido[2,1-
a]isoquinolin-2-ones 6a-c and X-Ray Structure of 6a a
N
NH
N
NH
N
NH
N
NH
O
Ph
O
O
O
3a
(24 h, 70%)
R
CN
Me
Et
bEtO
0.045 mL H2O
20 mol% KOH
b
3b
(48 h, 57%)
NH
3c
(8 h, 54%)
3d
(4 h, 33%)
Me
N
O
+
N
rt, 24 h
HN
N
N
NH
N
NH
O
5
2a,c,f
6a-c
R
O
O
O
Ph
Et
O
NC
3e
(24 h, 16%)
Me Me
N
O
3g
(24 h, 88%)
3f
(24 h, 56%)
Me
Me
N
O
N
O
Ph
Me
HN
HN
N
NH
HN
, 92%
6b
, 50%
N
NH
6c
, 72%
N
NH
O
6a
Ph
O
O
Ph
3i
O
3j
(24 h, 67%)
(24 h, 30%)
3h
(24 h, 47%)
SMe
Me
Cl
MeO
a Conditions: 5 (0.5 mmol), 2 (0.5 mmol), H2O (0.045 mL), 20
mol% KOH, rt
N
NH
N
NH
N
NH
Ph
O
Ph
3k
O
Ph
3m
O
An attempt to extend the reaction over the pyridine
b
(16 h, 16%)
3l
(24 h, 57%)
(120 h, 58%)
under similar conditions led to oligomeric products.24
a
Conditions: 1 (0.5 mmol), 2 (0.5 mmol), H2O (0.045 mL),
The annulation mechanism is assumed to start with
quinoline ring activation by reversible complexing of the
pyridine moiety with cyanoacetylenes to generate 1,3(4)-
b
20 mol% KOH, rt; due to the lethargic character of the
reaction at rt, it was necessary to carry out the annulation at
55-60 oC
dipolar intermediate
A (Scheme 5), in which the
heterocyclic system is positively charged at the nitrogen
atom and at C2, the latter might also have a higher LUMO
localization. The negative site of this dipolar intermediate,
being mainly concentrated at the carbon atom adjacent to
the CN moiety, is neutralized with a proton from water to
give intermediate B of the ammonium hydroxide type. The
strongly basic hydroxide anion (thus released) of this
The nature of substituents in the quinoline core also
considerably influences the yield of the target product and
the reaction time (cf. compounds 3g, i-m). The best yield of
88% is reached for the pyrimidoquinolinone 3g.
This is explained by the higher basicity of 3-
methylquinoline 1b compared to quinoline 1a (pKa for 1b
= 5.17 and pKa for 1a = 4.95, respectively) and, hence, a
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intermediate attacks the CN bond to produce intermediate as it is here exemplified by oxidation of pyrimido[1,2-
1
2
3
4
5
6
7
8
C with a nitrogen anionic center, which attacks the C(2)
atom to close the hydroxyl pyrimidine ring (intermediate
D), which then prototropically rearranges to the final
product.
a]quinolin-3-one 3g into SNHAr product 7 (Scheme 7).
Scheme 7. Dehydrogenation of 3g
Me
N
Me
NH
DDQ
Scheme
5.
Proposed
Pathway
for
the
Dihydropyrimidoquinolinone 3 Synthesis
DCM
rt, 4 h
N
N
Ph
O
Ph
O
2a
H2O
CN
7
, 43%
3g
CONCLUSION
In conclusion, we have disclosed the arylcyanoacetylene-
1a
OH
9
N
N
N
N
CN
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C
Ph
Ph
Ph
Ph
δ+
H
B
A
1,3-H shift
triggered,
KOH-assisted
construction
on
of
3a
dihydropyrimido[1,2-a]quinolin-3-ones
quinoline
N
N
N
N
platforms in water at room temperature. The reaction is
carried out in a two-phase aqueous organic system,
wherein hydroxide anion acts both as a catalyst and a
reactant. This water-driven, environmentally friendly
green synthesis features one-pot implementation, atom
economy and energy saving that meets the PASE
paradigm.25 In essence, the reaction studied is, in its key
step, an incomplete SNHAr process, which can be finalized
by external oxidation. The reactions provide rare, though
pharmaceutically valuable building blocks and potential
drug precursors, which may attract the interest of wide
circles of organic and medicinal chemists.
OH
Ph
OH
C
D
Probably the sequence A→D is realized in a shorter
concerted mode (Scheme 6) avoiding the formation of
nitrogen-centered anion C as kinetically independent
particle and the process represents a simultaneous
transfer of the electron pairs.
Scheme 6. Concerted Mode of Proposed Pathway
1,3-H shift
3a
D
N
N
N
N
EXPERIMENTAL SECTION
C
C
Ph
Ph
OH
OH
NMR spectra were recorded on a Bruker DPX-400
spectrometer (400.13 MHz for 1H and 100.62 MHz for
13C) in DMSO-d6 and CDCl3. Internal standards were
HMDS (for 1H nuclei δ 0.05 ppm) or residual solvent
signals (for 13C nuclei δ 77.16 ppm). The resonance signals
H
H
B
This mechanism is in keeping with the substituent
effects. Indeed, an electron-donating group in the quinoline
ring enhances its basicity and hence the concentration of
intermediate A facilitates the reaction like an electron-
acceptor in the cyanoacetylene molecules which makes the
triple bond more electrophilic. The catalytic role of KOH
can also be understood in term of Schemes 5/6, which
suppose as an important step hydroxide anion attack at the
CN bond.
of carbon atoms were assigned based on H−13C HSQC and
1
1H−13C HMBC experiments. Coupling constants (J) were
measured from one-dimensional spectra, and multiplicities
were abbreviated as follows: s (singlet), br. s (broad
singlet), d (doublet), dd (doublet of doublets), q (quartet), t
(triplet), m (multiplet). IR spectra were recorded on a two-
beam Bruker Vertex 70 spectrometer, in a microlyaer from
chloroform or in tablets with KBr. Elemental analysis was
carried out on a FLASH EA 1112 Series analyzer. Mass
spectra were recorded on an Agilent 6210 HRMS-TOF-ESI
Mass spectrometer. Electrostatic sputtering, registration of
positive ions. Sample Solvent - MeCN with the addition of
0.1% heptafluorobutanoic acid and with the addition of
calibration mixture for mass spectrometer. Melting points
were determined on a Kofler hot stage apparatus.
Commercial samples of quinolines 1a-c, acetylene 2a and
isoquinoline 5 were used. Quinolines 1d,e were prepared
by methylation of the corresponding hydroxyl and
mercapto quinolines.26 Samples of arylcyanoacetylenes 2b-
f were obtained according to reported methods.20a
Products 3a-m and 6a-c were separated and purified by
recrystallization from MeCN or EtOH or column
chromatography. Column and thin-layer chromatography
were carried out on silica gel (0.06-0.2 mm) with
chloroform/toluene/ethanol (20:4:1) mixtures as eluent.
Given the two-phase character of the reaction mixture, a
particular role of the micellar catalysis should not be
neglected. In fact, the reaction occurs in the organic phase
representing
a
continuum of droplets (kind of
microreactors) wherein the concentration of the reactants
and the catalysts (quinolines, cyanoacetylenes, H2O, KOH)
and their spatial orientation are different from those which
are outside, i.e. in the aqueous phase. The importance of
this phenomena is experimentally supported (Table 1,
entry 8), wherein a drastic drop of the target product yield
is observed for the ‘homogeneous protocol’.
The
cyanoacetylene-triggered
assembly
of
dihydropyrimido[1,2-a]quinolin-3-ones on the quinoline
scaffold represents, in its key step, intramolecular
nucleophilic hydrogen substitution at C2 of the azine ring
and, consequently, the dihydro derivatives formed (3) are
actually the intermediates of this incomplete SNHAr
process. The latter can be completed by the treatment of
dihydro intermediates with an external oxidant, e.g. DDQ
General Procedures
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Method A. A mixture of quinoline 1 (1 equiv.), acetylene
1-(4-Ethylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3c). Method B. From a mixture of
quinoline (1a) (65 mg, 0.5 mmol), acetylene 2c (78 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
in 0.2 mL of MeCN (8 h) product 3c (81 mg, 54%) was
1
2
3
4
5
6
7
8
2 (1 equiv.), H2O (5 equiv.), KOH (20 mol%) was stirred at
20-25 oC for appropriate time. After that the reaction
mixture was washed consequently with Et2O (5 × 1 mL)
and MeCN (2 × 1 mL) to separate the main part of
pyrimidoquinoline 3. Concentrated organic layers were
passed through the chromatography column to deliver 2-
aryl-3-cyanoquinoline 4, initial qiunoline 1 and remains of
target pyrimidoquinoline 3.
o
obtained as a light-yellow powder, mp 270-272 C (EtOH).
Initial quinoline (1a) (14 mg, conversion was 79%) and
acetylene 2c (14 mg, conversion was 82%) were
recovered. IR (microlyaer): 1600, 1652 (C=C, C=O) cm-1. 1H
NMR (400.13 MHz, CDCl3): δ 7.53-7.51 (m, 2H, H2’,6’ from
Ar), 7.22-7.20 (m, 2H, H3’,5’ from Ar), 7.05 (d, J7,8 = 9.0 Hz,
1H, H-7), 6.84-6.76 (m, 3H, H-6, H-8, H-9), 6.22 (d, J9,10
Method B. A mixture of quinoline 1 (1 equiv.), acetylene
2 (1 equiv.), H2O (5 equiv.), KOH (20 mol%) in small
amounts of MeCN (for homogenization of reaction
9
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
=
o
8.0 Hz, 1H, H-10), 6.15 (s, 1H, H-2), 6.04 (br. s, 1H, NH),
mixture) was stirred at 55-60 C for the appropriate time.
5.86 (dd, 3J5,6 = 9.8 Hz, 3J4a,5 = 4.6 Hz, 1H, H-5), 5.76-5.74 (m,
After that the reaction mixture was cooled to room
tempetature, washed consequently with Et2O (5 × 1 mL)
and MeCN (2 × 1 mL) to separate the main part of
pyrimidoquinoline 3. Concentrated organic layers passed
through the chromatography column to deliver 2-aryl-3-
cyanoquinoline 4, initial qiunoline 1 and remains of target
pyrimidoquinoline 3.
3
1H, H-4a), 2.66 (q, JH,H = 7.6 Hz, 2H, CH2 from Et), 1.23 (t,
3H, Me from Et) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ
164.8 (C-3), 153.9 (C-1), 147.6 (C4’ from Ar), 137.7 (C-10a),
131.9 (C1’ from Ar), 130.2 (C-6), 129.3 (C-9), 128.9 (C3’,5’
from Ar), 127.9 (C-7), 127.5 (C2’,6’ from Ar), 121.8 (C-6a),
121.1 (C-8), 118.2 (C-5), 117.6 (C-10), 111.3 (C-2), 65.0 (C-
4a), 28.9 (CH2 from Et), 15.4 (Me from Et) ppm. HRMS
(ESI-TOF): m/z [M+H]+ Calcd for C20H19N2O+: 303.1492;
found: 303.1493.
1-Phenyl-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-
3-one (3a). Method A. From a mixture of quinoline (1a)
(65 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5 mmol), H2O
(45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%) (24 h)
product 3a (96 mg, 70%) was obtained as a light-yellow
1-(4-Ethoxyphenyl)-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3d). Method B. From a mixture of
quinoline (1a) (45 mg, 0.35 mmol), acetylene 2d (60 mg,
0.35 mmol), H2O (32 mg, 1.75 mmol) and KOH (4 mg, 20
mol%) in 0.2 mL of MeCN (4 h) product 3d (37 mg, 33%)
o
powder, mp 267-268 C (washed with Et2O and MeCN).
Initial quinoline (1a) was recovered (13 mg, conversion
was 79%). IR (KBr): 1631 (C=C), 1653 (C=O) cm-1. 1H NMR
(400.13 MHz, DMSO-d6): δ 8.10 (s, 1H, NH), 7.63-7.61 (m,
2H, Ho from Ph), 7.46-7.44 (m, 3H, Hm,p from Ph), 7.17-7.15
(m, 1H, H-7), 6.85-6.79 (m, 3H, H-6, H-8, H-9), 6.14 (s, 1H,
H-2), 6.11-6.09 (m, 1H, H-10), 5.96 (dd, 3J5,6 = 10.0 Hz, 3J4a,5
o
was obtained as a grey-brown powder, mp 224-227 C
1
(EtOH). IR (microlyaer): 1604, 1657 (C=C, C=O) cm-1. H
NMR (400.13 MHz, CDCl3): δ 7.54-7.52 (m, 2H, H2’,6’ from
3
Ar), 7.04 (d, J7,8 = 9.0 Hz, 1H, H-7), 6.89-6.86 (m, 2H, H3’,5’
3
from Ar), 6.83-6.75 (m, 3H, H-6, H-8, H-9), 6.44 (br. s, 1H,
= 5.4 Hz, 1H, H-5), 5.73 (d, J4a,5 = 5.4 Hz, 1H, H-4a) ppm.
3
NH), 6.23 (d, J9,10 = 8.0 Hz, 1H, H-10), 6.09 (s, 1H, H-2),
Due to a poor dissolving of 3a in any solvents there is no
chanse to check 13C NMR spectrum. HRMS (ESI-TOF): m/z
[M+H]+ Calcd for C18H15N2O+: 275.1179; found: 275.1179.
5.88 (dd, 3J5,6 = 9.8 Hz, 3J4a,5 = 4.6 Hz, 1H, H-5), 5.74-5.72 (m,
1H, H-4a), 4.04 (q, 3JH,H = 7.2 Hz, 2H, CH2 from OEt), 1.41 (t,
3H, Me from OEt) ppm. 13C{1H} NMR (100.62 MHz, CDCl3):
δ 165.1 (C-3), 161.3 (C4’ from Ar), 153.6 (C-1), 137.8 (C-
10a), 130.1 (C-6), 129.2 (C-9), 129.0 (C3’,5’ from Ar), 127.9
(C-7), 126.6 (C1’ from Ar), 121.9 (C-6a), 121.1 (C-8), 118.2
(C-5), 117.7 (C-10), 115.3 (C2’,6’ from Ar), 110.2 (C-2), 64.9
(C-4a), 63.8 (CH2 from OEt), 14.9 (Me from OEt) ppm.
Also side 2-phenylquinoline-3-carbonitrile (4a) (6
o
mg, 5%) was isolated as a white powder, mp 197-198 C
(ethanol).22a 1H NMR and IR spectra are similar to the
literature data.27
1-(4-Methylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3b). Method A. From a mixture of
quinoline (1a) (65 mg, 0.5 mmol), acetylene 2b (71 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
(48 h) product 3b (82 mg, 57%) was obtained as a light-
+
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C20H19N2O2 :
319.1441; found: 319.1439.
4-(3-Oxo-4,4a-dihydro-3H-pyrimido[1,2-a]quinolin-
1-yl)benzonitrile (3e). Method A. From a mixture of
quinoline (1a) (65 mg, 0.5 mmol), acetylene 2e (76 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
(24 h) product 3e (24 mg, 16%) was obtained as an yellow
powder, mp 272-274 oC (MeCN). Initial quinoline (1a) was
recovered (29 mg, conversion was 55%). IR (microlyaer):
o
yellow powder, mp 265-266 C (EtOH). Initial quinoline
(1a) (26 mg, conversion was 60%) and acetylene 2b (7 mg,
conversion was 90%) were recovered. IR (microlyaer):
1
1607, 1657 (C=C, C=O) cm-1. H NMR (400.13 MHz, CDCl3):
δ 7.50-7.48 (m, 2H, H2’,6’ from Ar), 7.19-7.17 (m, 2H, H3’,5’
3
from Ar), 7.04 (d, J7,8 = 9.2 Hz, 1H, H-7), 6.84-6.75 (m, 3H,
1
1600, 1651 (C=C, C=O), 2225 (CN) cm-1. H NMR (400.13
3
H-6, H-8, H-9), 6.70 (br. s, 1H, NH), 6.21 (d, J9,10 = 7.9 Hz,
MHz, CDCl3): δ 7.73-7.67 (m, 4H, H2’,3’,5’,6’ from Ar), 7.09 (d,
3J7,8 = 9.0 Hz, 1H, H-7), 6.88-6.80 (m, 3H, H-6, H-8, H-9),
6.54 (br. s, 1H, NH), 6.24 (s, 1H, H-2), 6.06 (d, 3J9,10 = 8.0 Hz,
3
3
1H, H-10), 6.13 (s, 1H, H-2), 5.89 (dd, J5,6 = 9.6 Hz, J4a,5
=
4.8 Hz, 1H, H-5), 5.75-5.73 (m, 1H, H-4a), 1.23 (s, 3H, Me)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 165.0 (C-3),
153.8 (C-1), 141.2 (C4’ from Ar), 137.6 (C-10a), 131.7 (C1’
from Ar), 130.1 (C-6; C3’,5’ from Ar), 129.1 (C-9), 127.9 (C-
7), 127.4 (C2’,6’ from Ar), 121.9 (C-6a), 121.1 (C-8), 118.1
(C-5), 117.7 (C-10), 111.2 (C-2), 65.0 (C-4a), 21.6 (Me)
ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C19H17N2O+:
289.1335; found: 289.1349.
3
3
1H, H-10), 5.91 (dd, J5,6 = 9.8 Hz, J4a,5 = 4.6 Hz, 1H, H-5),
5.78-5.76 (m, 1H, H-4a) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 163.9 (C-3), 151.5 (C-1), 138.6 (C1’ from Ar),
136.8 (C-10a), 133.2 (C3’,5’ from Ar), 130.2 (C-6), 129.4 (C-
9), 128.3 (C-7), 128.0 (C2’,6’ from Ar), 122.0 (C-6a), 121.9
(C-8), 118.3 (C4’ from Ar), 117.7 (C-5), 117.5 (C-10), 114.3
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The Journal of Organic Chemistry
Page 6 of 10
(CN), 114.2 (C-2), 65.1 (C-4a) ppm. HRMS (ESI-TOF): m/z
128.1 (C-9), 127.7 (C2’,6’ from Ar), 127.2 (C-6), 126.7 (C-5),
[M+H]+ Calcd for C19H14N3O+: 300.1131; found: 300.1129.
125.4 (C-7), 122.9 (C-6a), 121.5 (C-8), 117.5 (C-10), 113.2
(C-2), 69.2 (C-4a), 26.8 [Me from C(O)Me], 19.5 (5-Me)
1
2
3
4
5
6
7
8
1-(4-Acetylphenyl)-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3f). Method A. From a mixture of
quinoline (1a) (65 mg, 0.5 mmol), acetylene 2f (85 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
(24 h) product 3f (88 mg, 56%) was obtained as an yellow
+
ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C21H19N2O2 :
331.1441; found: 331.1443.
6-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3i). Method A. From a mixture of
quinoline 1c (72 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
(24 h) product 3i (43 mg, 30%) was obtained as a light-
o
powder, mp 239-241 C (EtOH). Initial quinoline (1a) was
recovered (23 mg, conversion was 65%). IR (microlyaer):
1
1603, 1661 (C=C, C=O) cm-1. H NMR (400.13 MHz, CDCl3):
9
o
δ 7.98-7.96 (m, 2H, H3’,5’ from Ar), 7.72-7.70 (m, 2H, H2’,6’
from Ar), 7.08-7.06 (m, 1H, H-7), 6.84-6.80 (m, 3H, H-6, H-
8, H-9), 6.57 (br. s, 1H, NH), 6.24 (s, 1H, H-2), 6.14-6.11 (m,
beige powder, mp 229-235 C (washed with Et2O, MeCN).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
IR (microlyaer): 1651 (C=C, C=O) cm-1. H NMR (400.13
MHz, CDCl3): δ 7.62-7.61 (m, 2H, Ho from Ph), 7.43-7.36 (m,
3H, Hm,p from Ph), 7.26-7.23 (m, 1H, H-7), 6.85-6.82 (m, 2H,
H-8, H-9), 6.24-6.22 (m, 1H, H-10), 6.18 (s, 1H, H-2), 6.16
(br. s, 1H, NH), 5.74-5.69 (m, 2H, H-5, H-4a), 2.19 (s, 3H,
Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.9 (C-3),
154.0 (C-1), 137.6 (C-10a), 135.5 (C-6), 134.6 (Ci from Ph),
130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.9 (C-9), 127.4
(Co from Ph), 124.5 (C-7), 123.4 (C-6a), 121.0 (C-8), 118.2
(C-10), 115.2 (C-5), 112.0 (C-2), 64.9 (C-4a), 19.0 (Me)
ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C19H17N2O+:
289.1335; found: 289.1333.
3
3
1H, H-10), 5.91 (dd, J5,6 = 9.6 Hz, J4a,5 = 4.8 Hz, 1H, H-5),
5.80-5.78 (m, 1H, H-4a), 2.60 [s, 3H, Me from C(O)Me] ppm.
13C{1H} NMR (100.62 MHz, CDCl3): δ 197.4 [C=O from
C(O)Me], 164.2 (C-3), 152.4 (C-1), 138.9 (C1’ from Ar),
138.7 (C4’ from Ar), 137.1 (C-10a), 130.2 (C-6), 129.4 (C-9),
129.3 (C3’,5’ from Ar), 128.2 (C-7), 127.6 (C2’,6’ from Ar),
121.9 (C-6a), 121.6 (C-8), 117.9 (C-5), 117.5 (C-10), 113.5
(C-2), 65.1 (C-4a), 26.9 [Me from C(O)Me] ppm. HRMS
+
(ESI-TOF): m/z [M+H]+ Calcd for C20H17N2O2 : 317.1285;
found: 317.1281.
5-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3g). Method A. From a mixture of
quinoline 1b (143 mg, 1.0 mmol), acetylene 2a (127 mg,
1.0 mmol), H2O (90 mg, 5.0 mmol) and KOH (12 mg, 20
mol%) (24 h) product 3g (254 mg, 88%) was obtained as
an yellow powder, mp 280-282 oC (MeCN). IR
8-Methyl-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3j). Method A. From a mixture of
quinoline 1d (72 mg, 0.5 mmol), acetylene 2a (64 mg, 0.5
mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20 mol%)
(24 h) product 3j (96 mg, 67%) was obtained as an yellow
o
powder, mp 213-216 C (MeCN). IR (KBr): 1629, 1651
1
1
(microlyaer): 1650 (C=C, C=O) cm-1. H NMR (400.13 MHz,
(C=C, C=O) cm-1. H NMR (400.13 MHz, CDCl3): δ 7.62-7.60
CDCl3): δ 7.62-7.60 (m, 2H, Ho from Ph), 7.42-7.35 (m, 3H,
Hm,p from Ph), 7.00-6.98 (m, 1H, H-7), 6.81 (br. s, 1H, NH),
6.77-6.75 (m, 2H, H-8, H-9), 6.51 (s, 1H, H-6), 6.19 (s, 1H,
H-2), 6.18-6.16 (m, 1H, H-10), 5.55 (d, 3J4a,4 = 2.4 Hz, 1H, H-
4a), 2.07 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 165.4 (C-3), 153.8 (C-1), 136.3 (C-10a), 134.6 (Ci
from Ph), 130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.1 (C-
9), 127.5 (Co from Ph), 127.0 (C-7), 126.5 (C-5), 125.6 (C-
6), 122.8 (C-6a), 121.2 (C-8), 117.8 (C-10), 111.7 (C-2),
69.2 (C-4a), 19.5 (Me) ppm. HRMS (ESI-TOF): m/z [M+H]+
Calcd for C19H17N2O+: 289.1335; found: 289.1335.
(m, 2H, Ho from Ph), 7.42-7.36 (m, 3H, Hm,p from Ph), 6.87
(s, 1H, H-7), 6.75 (d, 3J5,6 = 10.5 Hz, 1H, H-6), 6.63 (d, 3J9,10
=
7.6 Hz, 1H, H-9), 6.48 (br. s, 1H, NH), 6.14 (s, 1H, H-2), 6.08
3
3
3
(d, J9,10 = 7.6 Hz, 1H, H-10), 5.88 (dd, J5,6 = 10.5 Hz, J4a,5
=
5.0 Hz, 1H, H-5), 5.75-5.74 (m, 1H, H-4a), 2.16 (s, 3H, Me)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.8 (C-3),
153.9 (C-1), 135.1 (C-10a), 134.7 (Ci from Ph), 130.8 (Cp
from Ph), 130.6 (C-8), 130.2 (C-9), 129.8 (C-6), 129.3 (Cm
from Ph), 128.5 (C-7), 127.5 (Co from Ph), 121.8 (C-6a),
118.0 (C-10), 117.7 (C-5), 111.5 (C-2), 65.1 (C-4a), 20.4
(Me) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for
C19H17N2O+: 289.1335; found: 289.1344.
Also side 2-phenylquinoline-3-carbonitrile (4g) (12
o
mg, 5%) was isolated as a white powder, mp 197-198 C
8-Chloro-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3k). Method B. From a mixture of
quinoline 1e (163 mg, 1.0 mmol), acetylene 2a (127 mg,
1.0 mmol), H2O (90 mg, 5.0 mmol) and KOH (12 mg, 20
mol%) in 0.2 mL of MeCN (16 h) product 3k (48 mg, 16%)
(ethanol).22a 1H, 13C NMR and IR spectra are similar to the
literature data.27
1-(4-Acetylphenyl)-5-methyl-4,4a-dihydro-3H-
pyrimido[1,2-a]quinolin-3-one (3h). Method A. From a
mixture of quinoline 1b (72 mg, 0.5 mmol), acetylene 2f
(85 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg,
20 mol%) (24 h) product 3h (77 mg, 47%) was obtained as
an yellow powder, mp 256-258 oC (MeCN). Initial quinoline
1b was recovered (35 mg, conversion was 51%). IR
(microlyaer): 1603, 1659 (C=C, C=O) cm-1. 1H NMR (400.13
MHz, CDCl3): δ 7.96-7.94 (m, 2H, H3’,5’ from Ar), 7.71-7.69
(m, 2H, H2’,6’ from Ar), 7.42 (br. s, 1H, NH), 7.01-6.99 (m,
1H, H-7), 6.77-6.76 (m, 2H, H-8, H-9), 6.52 (s, 1H, H-6),
6.25 (s, 1H, H-2), 6.10-6.09 (m, 1H, H-10), 5.56-5.55 (m,
1H, H-4a), 2.59 [s, 3H, Me from C(O)Me], 2.09 (s, 3H, 5-Me)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 197.4 [C=O from
C(O)Me], 165.2 (C-3), 152.3 (C-1), 138.9 (C1’ from Ar),
138.6 (C4’ from Ar), 135.9 (C-10a), 129.3 (C3’,5’ from Ar),
o
was obtained as a light-beige powder, mp 264-266 C
(MeCN, EtOH). Initial quinoline 1e was recovered (58 mg,
conversion was 64%). IR (KBr): 1634 (C=C), 1656 (C=O)
1
cm-1. H NMR (400.13 MHz, DMSO-d6): δ 8.18 (s, 1H, NH),
7.61 (m, 2H, Ho from Ph), 7.46 (m, 3H, Hm,p from Ph), 7.29
(s, 1H, H-7), 6.91 (m, 1H, H-6), 6.85-6.84 (m, 1H, H-9), 6.18
(s, 1H, H-2), 6.06 (m, 2H, H-5, H-10), 5.75 (m, 1H, H-4a)
ppm. Due to a poor dissolving of 3k in any solvents there is
no chanse to check 13C NMR spectrum. HRMS (ESI-TOF):
m/z [M+H]+ Calcd for C18H14ClN2O+: 309.0789; found:
309.0790.
Also side 6-chloro-2-phenylquinoline-3-carbonitrile
(4k) (47 mg, 18%) was isolated as a white powder, mp
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The Journal of Organic Chemistry
o
3
3
197-198 C (ethanol).22a 1H, 13C NMR and IR spectra are
Ho from Ph, H-8), 7.79 (t, J6,7 = 8.0 Hz, J7,8 = 8.0 Hz, 1H, H-
similar to the literature data.27
7), 7.58-7.52 (m, 3H, Hm,p from Ph), 7.49 (d, J6,7 = 8.0 Hz,
3
1
2
3
4
5
6
7
8
1H, H-6), 2.63 (s, 3H, SMe) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 158.2 (C-2), 149.2 (C-8a), 141.1 (C-4), 137.7 [Ci
from C(2)-Ph], 137.6 (C-5), 132.8 [Cp from C(2)-Ph], 130.3
(C-7), 129.3 [Co from C(2)-Ph], 128.9 [Cm from C(2)-Ph],
127.3 (C-8), 125.4 (C-6), 124.2 (C-4a), 118.2 (CN), 105.3
(C-3), 16.6 (SMe) ppm. Anal. Calcd for C17H12N2S: C, 73.89;
H, 4.38; N, 10.14; S, 11.60. Found: C, 73.92; H, 4.36; N,
10.11; S, 11.63.
8-Methoxy-1-phenyl-4,4a-dihydro-3H-pyrimido[1,2-
a]quinolin-3-one (3l). Method A. From a mixture of
quinoline 1f (159 mg, 1.0 mmol), acetylene 2a (127 mg, 1.0
mmol), H2O (90 mg, 5.0 mmol) and KOH (12 mg, 20 mol%)
(24 h) product 3l (172 mg, 57%) was obtained as an
o
yellow powder, mp 243-245 C (EtOH). Initial quinoline 1f
was recovered (28 mg, conversion was 82%). IR
1
(microlyaer): 1655 (C=C, C=O) cm-1. H NMR (400.13 MHz,
9
CDCl3): δ 7.62-7.60 (m, 2H, Ho from Ph), 7.44-7.36 (m, 3H,
4-Phenyl-1,11b-dihydro-2H-pyrimido[2,1-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hm,p from Ph), 6.74 (d, 3J9,10 = 9.8 Hz, 1H, H-9), 6.63 (d, 4J6,7
=
a]isoquinolin-2-one (6a). Method A. From a mixture of
isoquinoline (5) (129 mg, 1.0 mmol), acetylene 2a (127
mg, 1.0 mmol), H2O (90 mg, 5.0 mmol) and KOH (12 mg, 20
mol%) (24 h) product 6a (252 mg, 92%) was obtained as
an yellow powder, mp 215-216 oC (EtOH). IR (microlayer):
4
2.8 Hz, 1H, H-7), 6.45 (s, 1H, NH), 6.39 (dd, J6,7 = 2.8 Hz,
3
3J5,6 = 9.4 Hz, 1H, H-6), 6.13 (s, 1H, H-2), 6.11 (d, J9,10 = 9.8
3
3
Hz, 1H, H-10), 5.93 (dd, J5,6 = 9.4 Hz, J4a,5 = 4.9 Hz, 1H, H-
5), 5.74-5.72 (m, 1H, H-4a), 3.67 (s, 3H, OMe) ppm. 13C{1H}
NMR (100.62 MHz, CDCl3): δ 164.9 (C-3), 154.2 (C-8),
154.0 (C-1), 134.7 (Ci from Ph), 131.1 (C-10a), 130.8 (Cp
from Ph), 130.1 (C-6), 129.4 (Cm from Ph), 127.6 (Co from
Ph), 122.8 (C-6a), 119.1 (C-9), 118.6 (C-10), 114.5 (C-5),
113.3 (C-7), 111.2 (C-2), 65.0 (C-4a), 55.7 (OMe) ppm.
1
1650 (C=C, C=O) cm-1. H NMR (400.13 MHz, CDCl3): δ
7.55-7.54 (m, 2H, Ho from Ph), 7.50-7.42 (m, 3H, Hm,p from
Ph), 7.34-7.32 (m, 1H, H-9), 7.30-7.28 (m, 1H, H-11), 7.27-
3
7.23 (m, 1H, H-10), 7.09-7.07 (m, 1H, H-8), 6.39 (s, J1,11b
=
3
0.2 Hz (theoretical), 1H, H-11b), 6.23 (d, J6,7 = 7.8 Hz, 1H,
H-6), 5.74 (s, 1H, H-3), 5.70 (br. s, 1H, NH), 5.55 (d, J6,7 =
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C19H17N2O2 :
+
3
305.1285; found: 305.1283.
7.8 Hz, 1H, H-7) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ
164.1 (C-2), 154.0 (C-4), 132.9 (Ci from Ph), 131.0 (Cp from
Ph), 130.6 (C-7a), 129.7 (C-6), 129.2 (Co from Ph), 129.0
(Cm from Ph), 127.1 (C-9), 127.0 (C-11), 126.2 (C-10),
125.6 (C-11a), 125.3 (C-8), 104.5 (C-3), 102.2 (C-7), 66.3
(C-11b) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for
C18H15N2O+: 275.1179; found: 275.1179.
Also
side
6-methoxy-2-phenylquinoline-3-
carbonitrile (4l) (23 mg, 9%) was isolated as a white
o
powder, mp 169-170 C (EtOH). IR (microlayer): 2216
(CN) cm-1. 1H NMR (400.13 MHz, CDCl3): δ 8.51 (s, 1H, H-4),
3
8.07 (d, J7,8 = 9.2 Hz, 1H, H-8), 7.97-7.95 (m, 2H, Ho from
Ph), 7.56-7.50 (m, 3H, Hm,p from Ph; 1H, H-7), 7.10 (d, 4J5,7
=
2.6 Hz, 1H, H-5), 3.96 (s, 3H, OMe) ppm. 13C{1H} NMR
(100.62 MHz, CDCl3): δ 159.0 (C-6), 155.9 (C-2), 145.2 (C-
8a), 142.6 (C-4), 137.9 (Ci from Ph), 131.5 (C-8), 129.9 (Cp
from Ph), 126.2 (Co from Ph), 128.8 (Cm from Ph), 126.4 (C-
4a), 126.2 (C-7), 118.3 (CN), 105.9 (C-3), 104.7 (C-5), 55.9
(OMe) ppm. Anal. Calcd for C17H12N2O: C, 78.44; H, 4.65; N,
10.76. Found: C, 78.38; H, 4.55; N, 10.85.
4-(4-Ethoxyphenyl)-1,11b-dihydro-2H-
pyrimido[2,1-a]isoquinolin-2-one (6b). Method A.
From a mixture of isoquinoline (5) (65 mg, 0.5 mmol),
acetylene 2c (78 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol)
and KOH (6 mg, 20 mol%) (24 h) product 6b (75 mg, 50%)
was obtained as a mustard powder, mp 214-216 oC
(MeCN). Initial isoquinoline (5) was recovered (29 mg,
conversion was 55%). IR (microlayer): 1649 (C=C, C=O)
cm-1. 1H NMR (400.13 MHz, CDCl3): δ 7.47-7.45 (m, 2H, H2’,6’
from Ar), 7.33-7.22 (m, 5H, H-9, H-10, H-11, H3’,5’ from Ar),
8-(Methylthio)-1-phenyl-4,4a-dihydro-3H-
pyrimido[1,2-a]quinolin-3-one (3m). Method A. From a
mixture of quinoline 1g (88 mg, 0.5 mmol), acetylene 2a
(64 mg, 0.5 mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg,
20 mol%) (120 h) product 3m (93 mg, 58%) was obtained
3
7.08 (d, J8,9 = 7.4 Hz, 1H, H-8), 6.38 (s, 1H, H-3), 6.26 (d,
3J6,7 = 7.8 Hz, 1H, H-6), 5.73 (s, 1H, H-11b), 5.57 (br. s, 1H,
3
3
o
NH), 5.54 (d, J6,7 = 7.8 Hz, 1H, H-7), 2.69 (q, JH,H = 7.8 Hz,
2H, CH2 from Et), 1.26 (t, 3H, Me from Et) ppm. 13C{1H}
NMR (100.62 MHz, CDCl3): δ 164.3 (C-2), 154.3 (C-4),
147.9 (C4’ from Ar), 130.8 (C-7a), 130.3 (C1’ from Ar), 129.8
(C-6), 129.4 (C2’,6’ from Ar), 128.7 (C3’,5’ from Ar), 127.4 (C-
9), 127.1 (C-11), 126.3 (C-10), 125.8 (C-11a), 125.4 (C-8),
104.1 (C-3), 102.2 (C-7), 66.4 (C-11b), 22.9 (CH2 from Et),
15.4 (Me from Et) ppm. HRMS (ESI-TOF): m/z [M+H]+
Calcd for C20H19N2O+: 303.1492; found: 303.1493.
as a light-yellow powder, mp 265-267 C (EtOH). Initial
quinoline 1g was recovered (19 mg, conversion was 78%).
1
IR (microlyaer): 1656 (C=C, C=O) cm-1. H NMR (400.13
MHz, CDCl3): δ 7.61-7.59 (m, 2H, Ho from Ph), 7.42-7.37 (m,
3
3H, Hm,p from Ph), 7.35 (d, J5,6 = 10.0 Hz, 1H, H-6), 6.79-
6.73 (m, 2H, H-8, H-9), 6.57 (br. s, 1H, NH), 6.20 (s, 1H, H-
2), 6.06 (d, 3J9,10 = 7.6 Hz, 1H, H-10), 5.95 (dd, 3J5,6 = 10.0 Hz,
3J4a,5 = 5.0 Hz, 1H, H-5), 5.75-5.73 (m, 1H, H-4a), 2.41 (s, 3H,
SMe) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 164.8 (C-
3), 153.8 (C-1), 138.0 (C-7), 136.5 (C-10a), 134.5 (Ci from
Ph), 130.8 (Cp from Ph), 129.4 (Cm from Ph), 128.9 (C-9),
127.3 (Co from Ph), 126.5 (C-6), 120.2 (C-6a, C-8), 117.7 (C-
10), 116.0 (C-5), 112.5 (C-2), 64.6 (C-4a), 16.8 (SMe) ppm.
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C19H17N2OS+:
321.1056; found: 321.1044.
4-(4-Acetylphenyl)-1,11b-dihydro-2H-pyrimido[2,1-
a]isoquinolin-2-one (6c). Method A. From a mixture of
isoquinoline (5) (65 mg, 0.5 mmol), acetylene 2c (85 mg,
0.5 mmol), H2O (45 mg, 2.5 mmol) and KOH (6 mg, 20
mol%) (24 h) product 6c (113 mg, 72%) was obtained as
an yellow powder, mp 227-229 oC (MeCN). Initial
isoquinoline (5) was recovered (16 mg, conversion was
75%). IR (microlayer): 1567, 1653, 1676 (C=C, C=O) cm-1.
1H NMR (400.13 MHz, CDCl3): δ 8.03-8.01 (m, 2H, H3’,5’ from
Ar), 7.67-7.65 (m, 2H, H2’,6’ from Ar), 7.35-7.26 (m, 3H, H-9,
Also
side
6-(methylthio)-2-phenylquinoline-3-
carbonitrile (4m) (10 mg, 7%) was isolated as a light-
o
beige powder, mp 157-160 C (EtOH). IR (microlayer):
1
2219 (CN) cm-1. H NMR (400.13 MHz, CDCl3): δ 9.08 (s,
3
3
H-10, H-11), 7.09 (d, J8,9 = 7.4 Hz, 1H, H-8), 6.41 (s, 1H, H-
1H, H-4), 7.97 (d, J7,8 = 8.0 Hz, 1H, H-8), 8.01-7.95 (m, 2H,
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3), 6.16 (d, 3J6,7 = 7.8 Hz, 1H, H-6), 5.80 (s, 1H, H-11b), 5.77
(br. s, 1H, NH), 5.59 (d, J6,7 = 7.8 Hz, 1H, H-7), 2.63 [s, 3H,
(1) (a) Fu, R.; Xu, X.; Dang, Q.; Chen, F.; Bai, X. Rapid Access to
3
Pyrimido[5,4-c]isoquinolines via a Sulfur Monoxide Extrusion
Reaction. Org. Lett. 2007, 9, 571-574. (b) Cho, H.
Dihydropyrimidine. Heterocycles 2013, 87, 1441-1479. (c)
Panday, A. K.; Mishra, P.; Jana, A.; Parvin, T.; Choudhury, L. H. J.
Synthesis of Pyrimidine Fused Quinolines by Ligand-Free Copper-
Catalyzed Domino Reactions. Org. Chem. 2018, 83, 3624-3632. (d)
Aparna, E. P.; Devaky, K. S. Advances in the Solid-Phase Synthesis
of Pyrimidine Derivatives. ACS Comb. Sci. 2019, 21, 35-68.
(2) Hermecz, I.; Vasvari-Debreczy, L.; Matyus, P. Bicyclic 6-6
Systems with One Ring Junction Nitrogen Atom:One Extra
Heteroatom 1:0 In Comprehensive Heterocyclic Chemistry, Vol. 8;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press:
London, 1996, Chap. 23, 563-595; and references therein.
(3) Hermecz, I. Chemistry of Benzologs of Pyrido[1,2-
a]pyrimidines: Part V of Series on Pyrido-oxazines, -diazines, and
thiazines In Advances in Heterocyclic Chemistry, Katritzky, A. R.
Ed., Academic Press, 1999, vol. 73, 177-274; and references
therein.
(4) (a) Suri, O. P.; Suri , K. A.; Gupta, B. D.; Satti, N. K. An
Unequivocal Synthesis of 4-Methyl-2-oxo-(2H)-pyrido-[1,2-
a]pyrimidines. Synth. Commun. 2002, 32, 741-746. (b) Jadhav, A.
G.; Halikar, N. K. Synthesis and Biological Activity of Pyrimido[1,2-
a]quinoline Moiety and Its 2-Substituted Derivatives. J. Phys.: Conf.
Ser. 2013, 423, 012007, 1-8. (c) Elattar, K. M.; Rabie, R.;
Hammouda, M. M. Recent Progress in the Chemistry of Bicyclic 6–
6 Systems: Chemistry of Pyrido[1,2-a]pyrimidines. Monatsh.
Chem. 2017, 148, 601-627. (d) Chen, L.; Huang, R.; Kong, L.-B.; Lin,
J.; Yan, S.-J. Facile Route to the Synthesis of 1,3-Diazahetero-Cycle-
Fused [1,2-a]Quinoline Derivatives via Cascade Reactions. ACS
Omega 2018, 3, 1126-1136.
(5) Vartale, S. P.; Halikar, N. K.; Pawar, Y. D. Design Synthesis,
Reactions and Pharmacological Properties of Some Novel Fused
Pyrimido[1,2-a]quinolines Moiety. J. Pharmacy Res. 2012, 5,
2672-2675.
(6) Mogle, P. P.; Hese, S. V.; Kamble, R. D.; Hebade, M. J.;
Ambhore, A. N.; Kadam, S. N.; Kadam, S. S.; Kamble, S. S.; Gacche, R.
N.; Dawane, B. S. Synthesis and Evaluation of 7,8,9,10-Tetrahydro-
1H-pyrimido[1,2-a]quinoline-2,5-dicarbonitrile Derivatives as
Aantimicrobial Agents. J. Chem. Pharm. Res. 2015, 7, 894-900.
(7) Kadin, S. B. 2-Amino-4-hydroxyquinolines. Ger. Offen. DE
2801248, Jul. 20, 1978; Chem. Abstr. 1978, 89, 146784.
(8) (a) De, P.; Baltas, M.; Bedos-Belval, F. Cinnamic Acid
Derivatives as Anticancer Agents-a Review. Curr. Med. Chem.
2011, 18, 1672-1703. (b) Peperidou, A.; Pontiki, E.; Hadjipavlou-
Litina, D.; Voulgari, E.; Avgoustakis, K. Multifunctional Cinnamic
Acid Derivatives. Molecules 2017, 22, 1247 (1-17).
(9) Baumann, M.; Baxendale, I. R. An Overview of the Synthetic
Routes to the Best Selling Drugs Containing 6-Membered
Heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265-2319.
(10) Toque, H. A. F.; Priviero, F. B. M.; Teixeira, C. E.; Perissutti,
E.; Fiorino, F.; Severino, B.; Frecentese, F.; Lorenzetti, R.; Baracat, J.
S., Santagada, V.; Caliendo, G.; Antunes, E.; De Nucci, G. Synthesis
and Pharmacological Evaluations of Sildenafil Analogues for
Treatment of Erectile Dysfunction. J. Med. Chem. 2008, 51, 2807-
2815.
1
2
3
4
5
6
7
8
Me from C(O)Me] ppm. 13C{1H} NMR (100.62 MHz, CDCl3):
δ 197.3 [C=O from C(O)Me], 163.8 (C-2), 152.8 (C-4), 139.0
(C1’ from Ar), 137.3 (C4’ from Ar), 130.5 (C-7a), 129.9 (C-6),
129.6 (C3’,5’ from Ar), 129.0 (C2’,6’ from Ar), 127.3 (C-9),
126.8 (C-11), 126.3 (C-10), 125.7 (C-11a), 125.6 (C-8),
105.9 (C-3), 103.0 (C-7), 66.5 (C-11b), 26.9 [Me from
C(O)Me] ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for
+
C20H17N2O2 : 317.1285; found: 317.1284.
9
Dehydrogenation of the 5-methyl-1-phenyl-4,4a-
dihydro-3H-pyrimido[1,2-a]quinolin-3-one (3g) to 5-
methyl-1-phenyl-3H-pyrimido[1,2-a]quinolin-3-one
(7). A mixture of dihydropyrimido[1,2-a]quinolin-3-one
3g (100 mg, 0.3 mmol), DDQ (79 mg, 0.3 mmol) and CH2Cl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
(1 mL) was stirred at 20-25 C during 4 h. Solvent was
evaporated at the reduce pressure. The solid was extracted
with MeCN (10×0.5 mL), then solvent was removed and
crude product was passed through the chromatography
column deliver to the pyrimido[1,2-a]quinolin-3-one 7 (37
mg, 43%) as a brown oil. Initial compound 3g was
recovered (43 mg, conversion was 57%). IR (microlyaer):
1631 (C=C, C=O) cm-1. 1H NMR (400.13 MHz, CDCl3): δ 7.69
3
(s, 1H, H-6), 7.59 (d, J7,8 = 7.6 Hz, 1H, H-7), 7.45-7.43 (m,
1H, Hp from Ph), 7.41-7.37 (m, 2H, Hm from Ph), 7.33-7.30
(m, 1H, H-9), 7.28-7.24 (m, 2H, Ho from Ph), 7.03-7.01 (m,
1H, H-8), 6.89 (d, 3J9,10 = 8.6 Hz, 1H, H-10), 6.56 (s, 1H, H-2),
2.49 (s, 3H, Me) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ
169.5 (C-3), 154.0 (C-4a), 151.0 (C-1), 135.4 (C-10a), 135.1
(C-6), 134.0 (C-5), 131.7 (Ci from Ph), 130.4 (Cp from Ph),
129.5 (Cm from Ph), 128.0 (C-9), 127.5 (Co from Ph), 127.3
(C-7), 126.1 (C-8), 124.5 (C-6a), 122.3 (C-10), 113.6 (C-2),
18.5 (Me) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for
+
C19H15N2O2 : 287.1179; found: 287.1180.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
1H and 13C NMR spectra for all new compounds (PDF),
crystallographic data of 6a (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: boris_trofimov@irioch.irk.ru (B.A.T.)
ORCID
Boris A. Trofimov: 0000-0002-0430-3215
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
(11) Kleemann, A.; Engel, J.; Kutscher, B.; Reicher, D. in
Pharmaceutical substances (syntheses, patents, applications),
Thieme, Stuttgart – New York, 2001, vol. 1, p. 31.
The authors declare no competing financial interest.
(12) Di Braccio, M.; Roma, G.; Leoncini, G. 1,2-Fused
Pyrimidines VII. 3-(Dialkylamino-1H-pyrimido[1,2-a]quinolin-1-
ones and 2-(Dialkylamino)-4H-pyrimido[2,1-a]isoqiunolin-4-ones
as Antiplatelet Compounds. Eur. J. Med. Chem., 1995, 30, 27-38.
(13) Adib, M.; Mollahosseini, M.; Yavari, H.; Sayahi, M. H.;
Bijanzadeh, H. R. Simple One-Pot Three-Component Synthesis of
2-Oxo-1,11b-dihydro-2H-pyrimido[2,1-a]isoquinolines. Synthesis
2004, No. 6, 861-864.
ACKNOWLEDGMENT
The main results were obtained with Baikal analytical centre
of collective using SB RAS. Mass spectra were performed by
A.V. Kuzmin in Shared Research Facilities for Physical and
Chemical Ultramicroanalysis LIN SB RAS.
(14) Chen, D.-Q.; Li, C.-M.; Tu, S.-J. 6-(4-Chlorophenyl)-9,9-di-
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1
2
3
4
R1
R1
CN
0.045 mL H2O
20 mol% KOH
+
N
NH
5
6
7
8
N
rt, 24-120 h
O
R2
R1 = H, 3-Me, 4-Me, 6-Me, 6-Cl, 6-OMe, 5-SMe;
R2 = H, Me, Et, OEt, CN, C(O)Me
R2
up to 88%
13 examples
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
ACS Paragon Plus Environment